Systems and methods for measuring neurologic function via odorant, audible and/or somatosensory stimulation

ABSTRACT

A system for evaluating neurologic dysfunction of a subject includes an odorant generator configured to deliver an odorant stimulation to the subject, an auditory generator configured to deliver an audible stimulation to the subject, a vibrotactile stimulator configured to generate a somatosensory stimulation to the subject, a plurality of electrodes configured to be attached to the subject at respective different locations, and at least one processor. The plurality of electrodes are configured to collect neural signals from the subject as a result of the odorant stimulation, the audible stimulation, and the somatosensory stimulation. The at least one processor is configured to process the neural signals from the plurality of electrodes and generate an assessment of neurologic dysfunction of the subject.

RELATED APPLICATION

This application claims the benefit of and priority to U.S. ProvisionalPatent Application No. 62/640,364 filed Mar. 8, 2018, the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

FIELD OF THE INVENTION

The present invention relates generally to systems and methods ofevaluating neurologic dysfunction.

BACKGROUND OF THE INVENTION

There is significant evidence that the sense of smell is disrupted bybrain dysfunction; changes in smell are some of the best predictors ofmild traumatic brain injury (mTBI) and neurodegenerative diseases (e.g.,Alzheimer's and Parkinson's Diseases). Changes in smell are sensitiveindicators of mTBI, even in the absence of radiographic evidence ofinjury.

Most of the extant scientific literature supporting the link betweenolfactory deficits and mTBI/neurodegenerative diseases is derived frombehavioral/perceptual olfactometry studies—at present the gold standard.In some patients, however, behavioral smell tests are not possible(i.e., the patient is unconscious, uncooperative or an infant). In thesesubjects, electrophysiological measures may be the best alternative,measures comparable to otoacoustic emissions and/or ABR tests ofhearing.

Neurological measures of olfactory function (olfactory evoked potentials(OEPs) and olfactory event-related potentials (OERPs)), which can bemeasured using quantitative electroencephalographic (qEEG) techniques,are highly correlated with the behavioral measures but are lessfrequently used and therefore less understood as indicators of mTBI andneurodegenerative diseases. OEPs and OERPs can be measured using scalpEEG electrodes. Using standard EEG methods, it is also possible tosimultaneously visualize cortical alpha band oscillations along with theOEPs and OERPs. Alpha band oscillations are generated by thalamicpacemaker cells and are present when the brain is unstimulated (i.e., is“idling”) and are believed to aid in detecting new, incoming sensorystimulation; alpha oscillations rapidly decrease when the brain isactivated by external sensory stimuli.

There remains a need for systems and methods that provide measures ofthe conduction of neural information from sensory receptors in the nosethrough diffuse projections within the brain.

SUMMARY

It should be appreciated that this Summary is provided to introduce aselection of concepts in a simplified form, the concepts being furtherdescribed below in the Detailed Description. This Summary is notintended to identify key features or essential features of thisdisclosure, nor is it intended to limit the scope of the invention.

Embodiments of the present invention include systems and methods thatuse olfactory stimulation, through natural sensory receptors and neuralpathways, to generate OEPs and OERPs (and to suppress alpha bandoscillations) in conjunction with multimodal assessment usingsomatosensory and/or auditory stimulation. Changes in olfactory functionare sensitive indicators of neurological function in and of themselves;however, by combining olfactory, somatosensory, and auditory measures,this approach provides a novel and powerful electrophysiological measureof brain neural function for use in detecting mTBI and/orneurodegenerative diseases, like Parkinson's and or Alzheimer's disease,that does not require behavioral responding from the test subject.

In some embodiments, the systems include an intranasal deliveryapparatus that is a handheld device. In other embodiments, theintranasal delivery apparatus is supported by a stand.

According to some embodiments of the present invention, a system formeasuring olfactory evoked potentials includes an air (or other gas)source (e.g., an air pump or pressurized air source) configured toprovide a first stream of clean, odorless control air, an odorantgenerator configured to generate a second stream of odorized air, and anintranasal delivery system. A first valve is coupled to the air sourceand to the intranasal delivery assembly, a second valve is coupled tothe odorant generator and to the intranasal delivery assembly, and acontroller is coupled to the first and second valves. The controller isconfigured to direct the first and second valves to selectively open andclose such that the first stream of odorless control air and the secondstream of odorized air can be selectively directed to the intranasaldelivery assembly to deliver an odorant stimulation to the subject viathe intranasal delivery assembly.

The odorant generator is configured to generate the second stream ofodorized air with a defined odorant concentration. In some embodiments,the odorant generator is configured to generate the second stream ofodorized air with a selected one of a plurality of different odorantconcentrations.

The controller is configured to direct the first and second valves toselectively open and close such that the odorant stimulation has anabrupt onset. The controller is also configured to direct the first andsecond valves to selectively open and close such that there is noperceptible disturbance of air flow to the subject.

In some embodiments, the intranasal delivery assembly includes a firsttube connected to the first valve, a second tube connected to the secondvalve, a third tube in fluid communication with the first and secondtubes via a first connector (e.g., a Y-connector, etc.), and first andsecond delivery tubes. Each delivery tube includes a proximal end and anopposite distal end, and the proximal end of each delivery tube is influid communication with the third tube via a second connector (e.g., aY-connector, etc.). A bung is secured to the distal end of each deliverytube, and each bung is configured to be inserted into a respectivenostril of the subject. In some embodiments, each bung has a generallycylindrical body with electrically conductive material, such as foil,attached to an outer surface of the body.

In some embodiments, the system also includes an auditory soundgenerator and communicates with the controller and delivers soundsthrough a transducer such as an earbud insert earphone, etc.

In some embodiments, the system also includes a somatosensory stimulatorthat communicates with the controller and delivers vibratory stimuli orelectrical stimuli to the skin through a vibrotactile stimulator or skinelectrodes that can be affixed to the hand, arm, leg, torso, or otherbody part.

In some embodiments, the system also includes a plurality of electrodesconfigured to be attached to the subject at respective differentlocations. Each electrode is configured to collect neural signals fromthe olfactory epithelium or different cortical areas in the brain of thesubject. The system also includes a signal processor configured toreceive and process the neural signals from the plurality of electrodes,and a signal amplifier configured to receive and amplify the neuralsignals from the plurality of electrodes prior to processing by thesignal processor.

In some embodiments, the odorant generator includes an odorant cartridgeconfigured to aerosolize a liquid odorant contained therewithin. Thecartridge may include a frangible container of the liquid odorant and aplunger configured to break the frangible container to release theliquid odorant.

According to some embodiments of the present invention, a system formeasuring neurologic function of a subject includes an odorant generatorconfigured to deliver an odorant stimulation to the subject, an auditorygenerator configured to deliver an audible stimulation to the subject,and at least one electrode configured to be attached to the subject. Theat least one electrode is configured to collect neural signals from thesubject as a result of the odorant stimulation and the audiblestimulation. The at least one electrode may include a plurality ofelectrodes configured to be attached to the subject at respectivedifferent locations. The system further includes at least one processorconfigured to process the neural signals from the at least one electrodeand generate an assessment of the neurologic function of the subject.

In some embodiments, the auditory generator is configured to deliver anaudible stimulation to the subject via one or more earbuds worn by thesubject. However, other types of audio devices may be utilized.

In some embodiments, the system may also include a vibrotactilestimulator configured to generate a somatosensory stimulation to thesubject. For example, the vibrotactile stimulator may be configured togenerate a somatosensory stimulation to skin of the subject. The atleast one electrode is configured to collect neural signals from thesubject as a result of the somatosensory stimulation. In someembodiments, somatosensory stimulation may be generated via electricalstimulation, such as electrodes attached to the skin of the subject.

In some embodiments, the odorant generator is a handheld intranasaldelivery assembly. In other embodiments, the odorant generator comprisesa mask configured to be placed over a face of the subject, such asnonresponsive (e.g., loss of consciousness) or uncooperative subjects(e.g., malingers or infants).

According to other embodiments of the present invention, a system formeasuring neurologic function of a subject includes, an odorantgenerator configured to deliver an odorant stimulation to the subject,an auditory generator configured to deliver an audible stimulation tothe subject, a vibrotactile stimulator configured to generate asomatosensory stimulation to the subject, a plurality of electrodesconfigured to be attached to the subject at respective differentlocations, and at least one processor. The plurality of electrodes areconfigured to collect neural signals from the subject as a result of theodorant stimulation, the audible stimulation, and the somatosensorystimulation. The at least one processor is configured to process theneural signals from the plurality of electrodes and generate anassessment of neurologic function of the subject.

According to other embodiments of the present invention, a method ofmeasuring neurologic function of a subject includes delivering anodorant stimulation to the subject, delivering an audible stimulation tothe subject, delivering a somatosensory stimulation to the subject,collecting neural signals from the subject via one or more electrodesattached to the subject as a result of the odorant stimulation, theaudible stimulation, and the somatosensory stimulation, and processingthe neural signals via at least one processor to generate an assessmentof neurologic function of the subject. In some embodiments, the odorantstimulation, the audible stimulation, and the somatosensory stimulationare delivered to the subject at substantially the same time. Anassessment of neurologic dysfunction of the subject, such as from mTBIor a concussion, can then be determined by comparing the generatedneurologic function assessment to a baseline of neurologic function forthe subject.

In some embodiments, the odorant stimulation, the audible stimulation,and the somatosensory stimulation are delivered to the subjectsequentially. In some embodiments, the audible stimulation and thesomatosensory stimulation are delivered to the subject before theodorant stimulation. In some embodiments, the audible stimulation andthe somatosensory stimulation are delivered to the subject after theodorant stimulation.

Embodiments of the present invention are advantageous because OEPs canbe measured in uncooperative (e.g., infants or malingers) or unconscioussubjects.

Embodiments of the present invention are also advantageous because OERPscan be measured. OERPs are responses of cortical and higher levelneurons to olfactory stimulation. The presence of OERPs can also beverified as changes in cortical alpha band oscillations, and changes inalpha band oscillations produced by sensory stimulation, including byodorant stimulation, have been shown to reflect mTBI. By using OERPs, itmay be possible to assess higher level, cognitive function/dysfunction.Inclusion of auditory and somatosensory stimulation, either before,simultaneous with, or following odorant stimulation will allowassessment of function in wider brain regions. Embodiments of thepresent invention are advantageous because, by integrating multisensorystimulation, a more comprehensive assessment of brain function todiagnose and monitor mTBI can be obtained.

It is noted that aspects of the invention described with respect to oneembodiment may be incorporated in a different embodiment although notspecifically described relative thereto. That is, all embodiments and/orfeatures of any embodiment can be combined in any way and/orcombination. Applicant reserves the right to change any originally filedclaim or file any new claim accordingly, including the right to be ableto amend any originally filed claim to depend from and/or incorporateany feature of any other claim although not originally claimed in thatmanner. These and other objects and/or aspects of the present inventionare explained in detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which form a part of the specification,illustrate various embodiments of the present invention. The drawingsand description together serve to fully explain embodiments of thepresent invention.

FIG. 1 illustrates a system for measuring OEPs, OERPs, auditory, andsomatosensory evoked potentials nearly simultaneously in a single testsession, according to some embodiments of the present invention.

FIG. 2 illustrates a portion of an intranasal delivery system that ispart of the system of FIG. 1, according to some embodiments of thepresent invention.

FIG. 3 illustrates the intranasal delivery system of FIG. 2 attached toa subject for the measurement of OEPs/OERPs.

FIG. 4A is a schematic diagram of the valve assembly and the intranasaldelivery system of FIG. 2, according to some embodiments.

FIG. 4B is a schematic diagram of the valve assembly and the intranasaldelivery system of FIG. 2, according to other embodiments.

FIG. 5 is a schematic diagram of an odorant generator that can beutilized with the system of FIG. 1, according to some embodiments of thepresent invention.

FIG. 6 is an illustration of an example scalp map (e.g., theinternational standard 10-20 map) of EEG electrode placements used tocollect neural signals in response to olfactory, auditory, andsomatosensory stimuli according to some embodiments of the presentinvention. Active sensors are indicated in red, ground sensors in green(A1 for OEP, Pz for OERP) and reference sensor as yellow.

FIGS. 7A-7B are schematic diagrams illustrating the use of a firststream of odorless control air and a second stream of odorized air inaccordance with embodiments of the present invention. FIG. 7Aillustrates an interstimulus interval where a subject's nose receivesthe first stream of odorless control air only, and the second stream ofodorized air is directed towards a vacuum line. FIG. 7B illustrates astimulation interval where the second stream of odorized air is brieflydirected to the subject's nose, and the first stream of odorless controlair is redirected towards the vacuum line.

FIG. 8 illustrates an exemplary square wave form of air and odorantflows where an airstream containing an odorant is inserted into anairstream of odorless air.

FIGS. 9A-9B illustrate an odorant cartridge that may be utilized withthe odorant generator of the system of FIG. 1, according to someembodiments of the present invention.

FIG. 9C illustrates plungers of an odorant cartridge that are configuredto mechanically break glass ampoules within the cartridge to releaseliquid phase odorant onto the absorbent material in the interior of thecartridge, according to some embodiments of the present invention.

FIG. 10 is a perspective view of a bung that can be utilized with theintranasal delivery assembly of FIG. 2, according to some embodiments ofthe present invention.

FIG. 11A illustrates a graph of odorant concentration vs. time of a“staircase” procedure that may be utilized to estimate the neuralthreshold for eliciting an OEP from a subject, showing changes in evokedpotential amplitude with increases in stimulus intensity.

FIG. 11B illustrates a graph of amplitude vs. odorant concentration withhypothetical (prophetic) changes in neural responding with odorantconcentration.

FIGS. 12A-12D illustrate graphs of mV vs. time (ms) of exemplary OEPindividual wave form data obtained using the system of FIG. 1.

FIGS. 13A-13C illustrate color-coded exemplary OERP individualtopographical heat map data using the system of FIG. 1.

FIG. 14 illustrates exemplary alpha wave oscillation data using thesystem of FIG. 1.

FIGS. 15A-15N illustrate exemplary alpha wave spectra grand mean datafrom a group of simulated subjects tested using the system of FIG. 1.

FIGS. 16A-16B illustrate exemplary alpha band suppression grand meandata from a group of hypothetical subjects tested using the system ofFIG. 1.

FIGS. 17A-17F illustrate exemplary multisensory individual data usingthe system of FIG. 1.

FIG. 18 is a flowchart that illustrates methods of evaluating neurologicdysfunction via odorant, audible and/or somatosensory stimulation,according to some embodiments of the present invention.

DETAILED DESCRIPTION

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Like numbers refer to like elementsthroughout. In the figures, certain layers, components or features maybe exaggerated for clarity, and broken lines illustrate optionalfeatures or operations unless specified otherwise. In addition, thesequence of operations (or steps) is not limited to the order presentedin the figures and/or claims unless specifically indicated otherwise.Features described with respect to one figure or embodiment can beassociated with another embodiment or figure although not specificallydescribed or shown as such.

It will be understood that when a feature or element is referred to asbeing “on” another feature or element, it can be directly on the otherfeature or element or intervening features and/or elements may also bepresent. In contrast, when a feature or element is referred to as being“directly on” another feature or element, there are no interveningfeatures or elements present. It will also be understood that, when afeature or element is referred to as being “secured”, “connected”,“attached” or “coupled” to another feature or element, it can bedirectly secured, directly connected, attached or coupled to the otherfeature or element or intervening features or elements may be present.In contrast, when a feature or element is referred to as being, forexample, “directly secured”, “directly connected”, “directly attached”or “directly coupled” to another feature or element, there are nointervening features or elements present. The phrase “in communicationwith” refers to direct and indirect communication. Although described orshown with respect to one embodiment, the features and elements sodescribed or shown can apply to other embodiments.

The term “circuit” refers to software embodiments or embodimentscombining software and hardware aspects, features and/or components,including, for example, at least one processor and software associatedtherewith embedded therein and/or executable by and/or one or moreApplication Specific Integrated Circuits (ASICs), for programmaticallydirecting and/or performing certain described actions, operations ormethod steps. The circuit can reside in one location or multiplelocations, it may be integrated into one component or may bedistributed, e.g., it may reside entirely or partially in a portablehousing, a workstation, a computer, a pervasive computing device such asa smartphone, laptop or electronic notebook, or partially or totally ina remote location away from a local computer or processor of arespective test unit or device or a pervasive computing device such as asmartphone, laptop or electronic notebook. If the latter, a localcomputer and/or processor can communicate over local area networks(LAN), wide area networks (WAN) and can include a private intranetand/or the public Internet (also known as the World Wide Web or “theweb” or “the Internet”). Systems and devices according to embodiments ofthe present invention can comprise appropriate firewalls and electronicdata interchange standards for HIPPA or other regulatory compliance. Inthe traditional model of computing, both data and software are typicallysubstantially or fully contained on the user's computer; in cloudcomputing, the user's computer may contain little software or data(perhaps an operating system and/or web browser), and may serve aslittle more than a display terminal for processes occurring on a networkof external computers. A cloud computing service (or an aggregation ofmultiple cloud resources) may be generally referred to as the “Cloud”.Cloud storage may include a model of networked computer data storagewhere data is stored on multiple virtual servers, rather than beinghosted on one or more dedicated servers. Data obtained by varioussystems and devices according to embodiments of the present inventioncan use the Cloud.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise.

As used herein, the terms “comprise”, “comprising”, “comprises”,“include”, “including”, “includes”, “have”, “has”, “having”, or variantsthereof are open-ended, and include one or more stated features,integers, elements, steps, components or functions but does not precludethe presence or addition of one or more other features, integers,elements, steps, components, functions or groups thereof. Furthermore,as used herein, the common abbreviation “e.g.”, which derives from theLatin phrase “exempli gratia,” may be used to introduce or specify ageneral example or examples of a previously mentioned item, and is notintended to be limiting of such item. The common abbreviation “i.e.”,which derives from the Latin phrase “id est,” may be used to specify aparticular item from a more general recitation.

As used herein, the term “and/or” includes any and all combinations ofone or more of the associated listed items and may be abbreviated as“/”.

As used herein, phrases such as “between X and Y” and “between about Xand Y” should be interpreted to include X and Y. As used herein, phrasessuch as “between about X and Y” mean “between about X and about Y.” Asused herein, phrases such as “from about X to Y” mean “from about X toabout Y.”

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

It will be understood that although the terms first and second are usedherein to describe various features or elements, these features orelements should not be limited by these terms. These terms are only usedto distinguish one feature or element from another feature or element.Thus, a first feature or element discussed below could be termed asecond feature or element, and similarly, a second feature or elementdiscussed below could be termed a first feature or element withoutdeparting from the teachings of the present invention.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

The term “about”, as used herein with respect to a value or number,means that the value or number can vary by +/−twenty percent (20%).

Olfactory neural pathways, originating in the nasal cavity, reach intothe central nervous system where they branch diffusely within the brain;these tracts play critical roles in the brain's most importantfunctions, including emotion, memory and executive function. As aconsequence, damage to any of these areas can result in changes incognitive, emotional and olfactory function (cf., Osborne-Crowley, 2016;Alosco et al., 2016). Research studies have repeatedly shown arelationship between olfactory dysfunction and traumatic brain injury(TBI) (Frasnelli et al., 2015; Caminiti et al., 2013; Drummond et al.,2015). Likewise, it is known that changes in olfactory function are someof the first, and most accurate predictors of the eventual onset ofParkinson's and Alzheimer's Diseases (cf., Doty, 2003; Berendse et al.,2011; Doty, 2012; Rahayel et al, 2012; Velayudhan et al., 2013; Behrmanet al., 2014). The contents of these documents are hereby incorporatedby reference as if recited in full herein. TBI is one of the most commoncauses of olfactory dysfunction, though most of the afflicted areunaware of the sensory deficit.

The term “olfactory evoked potential” (OEP) refers to the electricalneural responses generated by the response (neural receptor potentials)of olfactory receptors (in, and between, the main olfactory epitheliumin the nasal cavity and the olfactory bulb in the forebrain) to odorantstimulation. OEPs can be obtained using an electrode placed in theepithelium, nasal cavity, on the surface of the bridge of the nose, oron the scalp. The term “olfactory event related potential” (OERP) refersto the electrical neural responses generated in cortical neurons byneural electrical activity conducted from “lower” regions of theolfactory central nervous system (i.e., olfactory receptors andolfactory bulb). OERPs can be obtained from surface electrodes usingstandard electroencephalographic (EEG) electrodes, methods andinstrumentation.

A stimulus for evoking any neural evoked potential, whether it isolfactory, auditory, visual or somatosensory, is preferably a stimuluswith an abrupt onset. A preferred odorant stimulus for evoking sensoryevoked potentials can have an infinite rise time and offset—a perfectsquare wave.

The neurophysiological reason for the stimulus is that the neuralresponse from any one receptor is so small that it may not be seen abovenormal background physiological noise created by muscles, eye movement,etc. Therefore, to visualize the neural response above the backgroundnoise, one needs to see the summed activity of many olfactory receptorsactivated at precisely the same moment—then improve that by using signalaveraging to increase the signal-to-noise ratio. Therefore, anodorant/stimulus delivery with as close to an instantaneous onset andoffset is accomplished by embodiments of the present invention.

There is significant evidence that the sense of smell is disrupted byhead trauma, and that changes in smell are some of the best predictorsof TBI. Changes in smell are sensitive indicators of TBI, even in theabsence of radiographic evidence. Changes in olfactory function aresensitive indicators of neurodegenerative diseases; because of thesensitivity, some have argued that Parkinson's Disease is an olfactorydisease. Most of the data in the scientific literature supporting thelink between olfactory deficits and TBI and neurodegenerative diseasesare from behavioral/perceptual olfactometry studies.Electrophysiological measures of olfactory function (OEPs and OERPs) arehighly correlated with the behavioral measures, but are less frequentlyused and, therefore, less understood as indicators of neurologicdysfunction. The current scientific literature also suggests that thedegree of olfactory dysfunction following head trauma predicts/indicatesthe magnitude and, possibly, the location of TBI. These data areprimarily from behavioral measures.

Embodiments of the invention can provide olfactory function tests thathave clinical utility and may be used for patient screening, i.e., todeliver results that inform decisions about treatment of patients,potentially in conjunction with other testing. Embodiments of theinvention can use evaluation of olfactory function to assess whether apatient/user may have TBI. Degradation of olfactory function can also bea biomarker for other neurological conditions and neurodegenerativediseases.

Additional embodiments of the present invention can use multisensorystimulation, where auditory sounds and somatosensory vibrotactilestimuli are presented before, simultaneous with, or after the odorant.Multisensory stimulation will activate and assess function in widerbrain regions than olfactory stimulation alone.

FIG. 1 illustrates a system 10 for measuring OEP and OERP multimodalresponses, according to some embodiments of the present invention, andthat can be utilized with auditory and somatosensory stimuli generatingdevices (described below). The system 10 allows multisensory collectionon cooperative as well as nonresponsive (e.g., loss of consciousness) oruncooperative subjects (e.g., malingers or infants). The system 10includes an odorant generator 100, a valve assembly 200 for controllingdelivery of an odorant (e.g., phenyl ethanol, butanol, propanol,cinnamon, etc.), an intranasal delivery assembly 300 for delivering anodorant to a subject, a signal amplifier and processor 400, a computerwith display 500. The odorant generator 100, described further below,provides an odorant pulse to the valve assembly 200 and intranasaldelivery assembly 300. The intranasal delivery assembly 300, in additionto delivering an odorant to a subject, includes surface recordingelectrodes that collect neural signals from the olfactory epithelium ofthe subject.

The illustrated system 10 may be utilized with devices for generatingauditory and somatosensory stimuli, as described with respect to FIG. 5.For example, sounds are generated by an audio source and communicated toa person's ear via inputs 330, such as earbuds/earphones or via anacoustic transducer. The controller 120 can also direct one or moresomatosensory generators to generate somatosensory stimuli to the skinof a person via activation of a vibrotactile stimulator 340 (FIG. 5).

Neural signals collected by various electrodes attached to a person, forexample as shown in the electrode map 700 (FIG. 6), are sent toindividual channels on the amplifier/processor 400 for amplification. Inaddition, the amplifier/processor 400 may be configured to increase thesignal integrity of collected neural signals. The amplifier/processor400 may be an independent unit, as illustrated, or may be integratedinto the electrodes 310 a-310 f (FIG. 3). FIG. 6 illustrates a map 700exemplary locations for electrodes. However, other electrode placementconfigurations and other numbers (i.e., 5-25, 10-20, etc.) of electrodesmay be utilized in accordance with embodiments of the present invention.

The amplified neural signals are processed by the amplifier/processor400 to aid in the identification of neural signals from noise. Theamplifier/processor 400 can take inputs from a number of differentchannels/electrodes and, using digital signal processing, can filter andstore neural responses from signals from the electrode map 700.

The processed digital signals are then sent to a computer 500 foraveraging and formatting for display. The raw wave form data can beshown on the display and can be stored and further processed by thecomputer 500. The neural signals created when odorant, auditory, andsomatosensory stimuli are applied are very small compared with thebackground physiological noise which are created, for example, by muscleartifacts, the movement of blood, respiration etc. A single response ofa neuron, or even a group of neurons, can be obscured by such backgroundnoise. The computer 500 uses signal averaging software to display OEPs,OERPs, auditory and somatosensory responses. Signal averaging is asignal processing technique used to increase the strength of a signalrelative to noise that is obscuring it. By averaging a set of replicatemeasurements, the signal-to-noise ratio (S/N) will be increased, and thenoise will average to near zero (0), while the amplitude of thebiological signal will be increased. The computer 500 can also beconfigured to control the overall test system 10, including delivery ofmultisensory stimuli to a subject via the various devices (i.e., odorantgenerator 100, auditory generator 330, somatosensory generator 340).

FIGS. 2, 3, 4A, 4B illustrate an intranasal delivery assembly 300according to some embodiments of the present invention. The illustratedintranasal delivery assembly 300 is configured for birhinal odorantdelivery and includes a plurality of electrodes 310 a-310 f (FIG. 3) andtwo delivery tubes 302 a, 302 b for simultaneous odorant delivery toboth nostrils of a subject. At the end of each delivery tube 302 a, 302b is a respective bung 304 a, 304 b comprising an electricallyconductive outer layer such as conductive foil. Each bung 304 a, 304 bserves as an electrode for recording evoked potentials in a nasalcavity.

As illustrated in FIG. 10, each bung 304 a, 304 b has a body 320 with agenerally cylindrical configuration. The body 320 may be formed fromfoam or other elastomeric materials. A passageway 322 extends throughthe body 320 and terminates at an aperture 322 a in the distal end 320 aof the body 320, as illustrated. A hollow tube 324 extends outwardlyfrom the proximal end 320 b of the body 320 and is in fluidcommunication with the passageway 322. The tube 324 is configured to beinserted within, or otherwise attached to, one of the delivery tubes 302a, 302 b. Thus, when a bung 304 a, 304 b is attached to a respectivedelivery tube 302 a, 302 b, a generated odorant flows through therespective delivery tube 302 a, 302 b, through the hollow tube 324,through the passageway 322 in the body 320 of the bung 304 a, 304 b, andexits through the aperture 322 a into a nostril of a subject.

As illustrated in FIG. 10, each electrode bung 304 a, 304 b is coveredwith a conductive foil 326. Exemplary conductive foil includes copper orgold foil. However, any conductive foil may be utilized. Conductive gelmay be placed on the electrode bungs 304 a, 304 b, and the bungs 304 a,304 b are inserted as far as comfortable, mono- or bi-rhinally into thenose of the subject, as illustrated in FIG. 3. Electrically conductivetape 306 (FIG. 2), such as copper tape, etc., on each bung 304 a, 304 bis used to secure wire leads 308 that are connected to the amplifier400. The wire leads 308 may be electrically connected to the conductivetape via alligator clips, solder or the like.

Flow sensors 307 (FIGS. 4A-4B) may be coupled to the bungs 304 a, 304 bto detect the exhalation/inhalation pattern of a subject and to allowfully automated control of the odorant pulse delivery during subjectinhalations.

FIG. 3 illustrates the bungs 304 a, 304 b inserted within the nostrilsof a subject and the electrodes 310 a-310 f attached to the subject atvarious locations. Typically, a subject will be supine with eyes closed,and the locations on the subject's face where the electrodes 310 a-310 fwill be attached are scrubbed with disposable alcohol wipes to removeoils and dirt to improve conductivity and the attachment strength of theelectrode adhesive. In the illustrated embodiment of FIG. 3, four padelectrodes 310 a-310 d, such as Red Dot™ brand EKG electrodes, availablefrom 3M Company, Saint Paul, Minn., are attached bilaterally about 1centimeter off the midline, just above and just below the medial canthusof the subject. A reference electrode 310 e is placed on the forehead ofthe subject, and a ground electrode 310 f is placed on the left ear ofthe subject. These electrodes 310 a-310 f are attached via lead wires to“no-touch” connectors on the valve assembly box 200. The illustratedintranasal delivery assembly 300 is designed for single use and isdisposable.

A valve assembly device 200 (FIG. 1) is connected to the intranasaldelivery assembly 300 and controls the delivery of odorant to theintranasal delivery assembly 300. In some embodiments, the valveassembly device 200 may be a structure formed to approximate thecurvature of the human face and may be held against the face withelastic bands, etc. In other embodiments, the valve assembly device 200may be a handheld device.

In other embodiments, the valve assembly device 200 may be supported bya stand or other structure and is not held by a person being tested. Thevalve assembly device 200 holds a series of miniature solenoid valvesthat produce electromechanical stimuli when activated. Use of a stand orother structure to hold the valve assembly device 200 can preventinadvertent, uncontrolled mechanical and electrical stimulation of thehand and the mechanosensory neural system, which can result in unwantedcortical activity and confound interpretation of the desired odorantresponses. In some embodiments, the system of the present invention isdesigned to introduce specified and controlled somatosensory stimulationusing 0.2-2.0 ms square electrical pulses through surface electrodes onthe median nerve at the wrist, or vibrotactile stimulation on thefingers. As such, a stand or other structure supporting the valveassembly device 200 can eliminate the possibility of the valves causingunwanted stimulus to the person, particularly where it is desired tointroduce specified and controlled somatosensory stimulation and/orvibrotactile stimulation.

In other embodiments, the intranasal delivery assembly 300 may beconfigured as a mask that is placed over the face of a subject, such asa nonresponsive (e.g., loss of consciousness) subject or uncooperativesubjects (e.g., malingers or infants).

Referring to FIG. 4A, the interconnection of the valve assembly 200 andthe intranasal delivery assembly 300, according to some embodiments ofthe present invention, is illustrated. A continuous loop of a firststream of odorless filtered control air and a second stream of odorizedair are delivered to separate valves 202, 204 in the valve assembly 200through separate, dedicated lines. For example, the continuous loop ofthe first stream of odorless control air is delivered to the valve 204from an air source (e.g., an air pump, compressed air source, etc.) vialine 206 c and returned to a charcoal filter via line 206 d. Thecontinuous loop of the second stream of odorized air is delivered to thevalve 202 from an odorant generator via line 206 b and returned to acharcoal filter via line 206 a. In between odorant pulses, thecontinuous first stream of odorless control air is delivered to asubject via the intranasal assembly 300, while the second stream ofodorized air is shunted by valve 202 to the charcoal filter.

To interconnect the valve assembly 200 and the intranasal deliveryassembly 300, a first tube 220 is connected to the valve 202, a secondtube 222 is connected to the valve 204, and a third tube 226 is in fluidcommunication with the first and second tubes 220, 222 via a firstconnector 210, such as a Y-connector. The first Y-connector 210 joinsthe outputs of the two valves 202, 204 into the third tube 226, and asecond Y-connector 212 separates the airflow for odorant delivery to thetwo nostrils of the subject via the delivery tubes 302 a, 302 b of theintranasal delivery assembly 300.

At the initiation of a test sequence, valve 204 is fully open deliveringa continuous, clean, filtered airstream to the test subject, valve 202is closed blocking the flow of the odorized airstream. To deliver thetest odorant, valve 204 is closed, thereby routing the clean airstreamto the charcoal filter, at the same instant that valve 202 is opened toroute the odorized airstream to the test subject via the intranasalassembly 300 or for the duration of the odorant pulse (e.g., 200 to 800milliseconds, although other durations may be utilized). Another valve208 is provided for controlling a vacuum line 230 and is activated afterodorant delivery to evacuate residual odorized air from the nasalcavity. In some embodiments, the various tubes (e.g., delivery tubes 302a, 302 b, lines 206 a-206 d and 226) have a minimum internal diameter(ID) of about 3/16″. However, embodiments of the present invention arenot limited to tubes or connectors having a particular ID and/orconfiguration.

The system 10 of FIG. 1 is configured to automatically measure olfactoryevoked potentials and trigeminal evoked potentials. Chemically-evokedtrigeminal potentials are less, or not affected by neurological insult,so can be used to verify device function and ability to measure neuralsignal. If trigeminal OEP or OERP is the same, but olfactory (bothmeasured in the same session with a subject) is decreased, strongerolfactory evidence of neurologic insult exists. If only using olfactoryOEP and/or OERP measures and no neural signal observed, it may bedifficult to determine if a subject's neural system is bad or if therecording instrumentation system was not working properly. Concurrenttrigeminal measurement provides an inherent system check.

According to some embodiments of the present invention, and asillustrated in FIGS. 11A and 11B, a “staircase” procedure may beutilized to estimate the neural threshold for eliciting an OEP from asubject or to estimate that subject's odor sensitivity. Theconcentration staircase is an approach commonly used in measuringauditory evoked potentials. For example, FIGS. 11A and 11B present ahypothetical example Illustrating the effects of increasing odorantconcentration on the amplitude of olfactory on evoked potentials.

Changes in olfactory evoked potential amplitude with increases inodorant concentration (bottom to top waveforms) are illustrated in FIG.11A. At the lowest concentration, the evoked potential is not obvious,but by repeating the evoked potential with increasing odorantconcentration, the evoked potential response becomes apparent. When thegrowth in the amplitude of the evoked potential (FIG. 11B) is comparedin the same patient over time or across patients, it is possible toidentify impaired olfactory sensitivity (i.e., when the head is struckwith force, the skull moves immediately but there is a phase lag in theresponse of the brain, which can cause olfactory neurons passing fromthe olfactory epithelium through the cribriform plate to the olfactorybulb to be sheared decreasing sensitivity). Embodiments of the presentinvention utilize a similar procedure such that, by repeating the OEPwith increasing odorant concentrations, changes in function that mightserve as a biomarker for neurological insult can be identified.

According to some embodiments of the present invention, the odorantconcentration from OEP to OEP will be increased from, for example, 10%,then 20%, then 30% . . . up to 100%. The OEP will be measured at eachconcentration. For the lowest odorant concentrations, the OEP may be toosmall, and may not be visible over the neural background noise floor.However, as the odorant concentration is increased, the OEP signalamplitude will grow and become visible above the noise floor.Measurement continues to 100% odorant concentration, even if the OEPpeak is observed at much lower concentrations, and the higher levelpeaks can be used to verify the lower, near threshold, smaller peaks.Threshold can be defined in many ways, such as the first odorantconcentration where the OEP peak is 0.5 pV above the noise floor.

FIG. 11B illustrates hypothetical changes in neural responding withodorant concentration. The top trace illustrates an OEP at odorantconcentrations, and lower traces with progressive decreases in odorantconcentration. The lower the odorant concentration that an OEP can beobserved, the more sensitive the nose. Over time, or with neurologicalinsult, higher odorant concentrations, indicating a decrease inolfactory sensitivity, are required to evoke the same amplitudeOEP/OERP.

In general, OERP amplitude is not sensitive to odorant level, or in someembodiments OERPs will include measuring OERPs using odorant pulses ofthe same concentration.

Auditory sound stimuli and somatosensory vibrotactile stimuli can be ofa fixed, or varied amplitude.

FIG. 5 illustrates an odorant generator 100, an auditory generator 330,and a somatosensory generator 340 according to some embodiments of thepresent invention. In the illustrated embodiment, the odorant generator100 includes two valves 102 a, 102 b which control the airflows thatcreate the “odorant pathway” channel. Ambient air may be drawn through adesiccator 104 and a charcoal filter 106 via an air pump 107 that is influid communication with the valves 102 a, 102 b. The illustratedembodiment of the odorant generator 100 also includes a passive odorantcartridge 108 and odorant proportional valves 110 a, 110 b. Valve 102 acontrols the airflow through the passive odorant cartridge 108 toproduce a 100% saturated odorant, and forms the input to the odorantproportional valves 110 a, 110 b for mixing with the clean air dilutionpathway from valve 102 b. The passive odorant cartridge 108 is used toaerosolize the odorant and create a saturated airspace. The output fromthe of the passive odorant cartridge 108 is 100% saturated airflow. Inan additional embodiment, the cartridge is replaced by anebulizer/ultrasonicator. The odorant concentration generated may not be100% so long as the concentration is verifiable via a photo ionizationdetector, CMOS or the like, and repeatable from use to use.

In the illustrated embodiment, the two proportional valves 110 a, 110 bare used to produce variable specified odorant dilutions. Valve 110 a isin fluid communication with the passive odorant cartridge 108, and valve110 b is in fluid communication with clean air for diluting the odorantto a target odorant concentration. In some embodiments of the presentinvention, both valves 110 a, 110 b may be mounted in a manifold 112.

Using the illustrated two proportional valve arrangement, any odorantconcentration from 0 to 100% can be produced. The two valves 110 a, 110b control the release of the saturated odorant and air, respectively,and cause mixing of the odorant with the filtered air in the rightproportions to create the desired target concentration. In someembodiments of the present invention, a small mixing space may beutilized to make sure that an odorant is thoroughly mixed into anddiluted by the clean-air. These proportional valves 110 a, 110 b may becontrolled, for example, using a variable DC control signal.

In some embodiments, an odorant utilized by the odorant generator 100can comprise a gel odorant wherein the gel is held in a mesh/perforatedstructure, or in a polymer that can be released within a cartridge. Insome embodiments, a liquid phase odorant (e.g., from ampoules) may bedispensed, prior to use/on cartridge insertion, onto an absorbentdiaper-like material. In some embodiments, a multiple reservoircartridge that holds two or three different dilutions of an odorantcould be utilized.

Still referring to the embodiment illustrated in FIG. 5, a 3-way valve202 takes the target odorant in the specified dilution from the manifold112 and/or proportional valves 110 a, 110 b as one input, and clean,filtered air directly from the air pump 107 as the second input. Theflow rate of both the odorant and clean-air stream may be the same(e.g., about 8-10 liter per minute). The 3-way valve 204 can release acontinuous stream from the filtered air except when the target odorantpulse is to be delivered, when it will switch and deliver the targetodorant for 200 to 1000 milliseconds, then switch back and deliver theclean, filtered air flow. The switching from one to the other, and viceversa, may be on the order of about 1 to 5 milliseconds, for example,and should result in as close as possible to a square wave form as canbe achieved with airflows.

FIG. 8 illustrates a measured, exemplary square wave form where anodorant channel is presented into a gap where the fresh air channel hasbeen gated off, creating an odorant pulse duration of 600-800 ms withoutan overall change in air pressure detectable by a human observer.

Valves 202, 204 allow the delivery of a stimulus (i.e., odorant)embedded in a constantly flowing air stream such that subjects do notperceive the switching from odorless to odorized air. Subjects receive aconstant intranasal airflow (e.g., about 6 liter/minute) which ishumidified (e.g., about 80% relative humidity) and warmed to bodytemperature (e.g., about 36° C.) such that, following a short period ofadaptation, administration of the constant airflow is not perceived bythe subject.

Still referring to FIG. 5, test subject interface components 330 and 340complete the multisensory system, according to some embodiments of thepresent invention. Auditory sound stimuli created by a speaker under thedirection of the controller 120 is communicated to the test subject'sear by earbud transducers inserted into the external ear canal, or by anacoustic headphone speaker placed near the ear, etc. Sound stimuli maybe delivered at a moderate (˜70 dB SPL) level, although various decibellevels may be utilized. Somatosensory stimuli are created by avibrotactile stimulator (e.g., a vibration device attached to the body,such as the back of the hand, etc.) and under control by the controller120. Somatosensory evoked potentials can be evoked by vibrotactilestimulator, or a 0.2-2 millisecond duration electrical stimulus,delivered to surface electrodes on the medial nerve at the wrist.Tactors, such those as available from Engineering Acoustics, Inc.,Casselberry, Fla., can be attached to the finger tips, and can stimulateat 60 Hz, or a single square pulse.

FIG. 18 is a flow chart illustrating methods of measuring neurologicfunction according to some embodiments of the present invention. One ormore of an odorant stimulation (Block 1000), an audible stimulation(Block 1010), and a somatosensory stimulation (Block 1020) may bedelivered to a subject. In some embodiments, the odorant stimulation,the audible stimulation, and the somatosensory stimulation are deliveredto the subject sequentially. In some embodiments, the odorantstimulation, the audible stimulation, and the somatosensory stimulationare delivered to the subject substantially simultaneously. In someembodiments, the audible stimulation and the somatosensory stimulationare delivered to the subject before the odorant stimulation. In someembodiments, the audible stimulation and the somatosensory stimulationare delivered to the subject after the odorant stimulation. The odorantstimulation, audible stimulation, and somatosensory stimulation causethe generation of neural signals from the subject, and these neuralsignals are obtained (Block 1030) via electrodes attached to thesubject, e.g., attached to the scalp, etc. The neural signals areprocessed by one or more processors to generate an assessment ofneurologic function of the subject. An assessment of neurologicdysfunction of the subject, such as from mTBI or a concussion, can thenbe determined by comparing the generated neurologic function assessmentto a baseline of neurologic function for the subject. (Block 1040). Insome embodiments, a determination of the presence of a neurodegenerativedisease, the increased likelihood of eventual onset of aneurodegenerative disease, or the presence of mTBI can be judged bycomparison of a single neurological function to a demographic populationdatabase of similar olfactory evoked potentials.

The neural signals can be visualized using quantitativeelectroencephalography (qEEG). Sensory cortical evoked potentials (e.g.,olfactory, auditory and/or somatosensory) can be viewed directly asvoltage waveforms, or indirectly as changes in brain oscillations (e.g.,alpha, beta, gamma, theta, etc.) as shown in FIG. 14.

According to embodiments of the present invention, sensory neuralactivity evoked by odorant, auditory and/or somatosensory stimuli can bemeasured from electrodes, e.g., scalp electrodes. After recording theevoked neural responses, the neural responses can be measured directlyor by their effect on other brain responses, such as beta, theta and/oralpha band oscillations using qEEG. For example, when odorants arepresented to the nose, they produce significant suppression ordesynchronization of alpha band oscillations.

Concussions and mTBI can interfere with alpha band desynchronizationproduced by working memory tests. Working memory tests are typified byasking a person to repeat a sequence of numbers, then asking them torecall the number x or y before the last number. Working memory testsare behavioral and require active participation from the subject. Theseare affected by attention, education, language, cooperation, etc., orvariations in test conditions or examiner expertise. Embodiments of thepresent invention generate evoked sensory responses and do not requirecooperation from the subject.

Concussions and mTBI can be identified as either baseline-postconcussion comparisons of evoked responses (e.g., decreases in amplitudeof waveforms as shown in FIG. 12A-12D), decreases in spread or amplitudeof voltage gradients (e.g. as shown in FIG. 13), changes in the speed orlocation of current flow from one brain location to another (i.e.,current might not flow between two normal brain cortices if there ismTBI brain damage in between; see FIG. 15—where damage might preventflow between 15I and 15J), or the alpha band suppression present in theoval in FIG. 14 might be lost. The same or similar changes caused by theslower deterioration due to neurologic disease may be measurable, albeitover a longer time period (slow progression of a neurodegenerativedisease), hence a measure of “neurologic dysfunction.”

Referring to FIGS. 7A-7B, in order to embed brief odor pulses withinconstant air flow, two airstreams are produced. One contains odorlesscontrol air (C) whereas the other contains an odorant (O) at a definedconcentration. Different odor concentrations may be obtained byadjusting the dilution (D) of the odorant. A vacuum system (V) may beutilized, as well as a small cross current of odorless air, whichprevents molecules of the (O) tubing from being drawn into other tubes.

During the interstimulus interval (FIG. 7A), a subject's nose receivescontrol air only. The odorized (O+D) airstream is directed towards thevacuum (V) line and directed to the charcoal filter. During stimulation,the (O+D) airstream is briefly directed to the outlet of the stimulator,and control air is redirected towards the vacuum line (V) (FIG. 7B).Using this system, it is therefore possible to switch between anodorless and an odorized air stream in less than about 10 to 20milliseconds. Airflow rates are calibrated and the stimulus andno-stimulus conditions are controlled by the valves 202, 204 describedabove in FIG. 5. Subjects do not perceive the control air which ispresented during the interstimulus interval and the switching betweenodorless and odorized air is not accompanied by any mechanical orthermal changes in the airflow. However, it should be noted thatsubjects will feel the control air, just not changes/perturbations inthe flow rate of the control air. If the flow rate remains constant, themechanoreceptors will adapt and will not produce an electrical responsethat might modify the olfactory waveform. It is critical that the onlychanges in stimulation detected be the onset of the odorant by theolfactory receptors.

The various valves of the odorant generator 100 and the valve assembly200 illustrated in FIGS. 1 and 5 are controlled by a controller 120,such as an Intel NUC, Arduino, or a Raspberry Pi controller. Thecontroller 120 takes a USB input from a computer 500 (FIG. 1) andtriggers the odorant pulses. The controller 120 stores all stimulusinformation, including but not limited to, odorant duration, odorantconcentration, inter-odor pulse interval, etc. The final odorant linevalve 202 can send a voltage signal to the computer to verify preciselywhen the odorant pulse is delivered to the test subject.

The computer 500 (FIG. 1) or the controller 120 (FIG. 5) may havesoftware for performing signal averaging and signal processing tocomputationally increase the OEP/OERP waveform signal-to-noise ratio andaid in response detection, calculating of OEP/OERP response latency andamplitude. The computer 500 may also store subject Hx, responding andanalytics. The computer 500 may also run software to analyze EEGwaveforms utilizing standard software programs such as MatLAB(Mathworks, Natick, Mass.) EEGLab.

A vacuum pump 130 (FIG. 5) can be used to draw residual odorants througha charcoal filter 140, and limit contamination to and from theintranasal delivery assembly 300. The vacuum pump 130 can also beconfigured to assist in the creation of the odorant pulses with thethree-way valves 202, 204.

Referring now to FIGS. 9A and 9B, an odorant cartridge 800 which isconfigured to rapidly aerosolize an odorant and which can be utilized asthe passive odorant cartridge 108 in FIG. 5, is illustrated. Theillustrated cartridge 800 is a reservoir for creating/storing saturatedodorant. The cartridge 800 can contain a liquid phase odorant. Thecartridge protects against leakage and oxidation.

The illustrated cartridge 800 includes a filtered air inlet port 810 andan odorant saturated air outlet port 812, and the inlet port 810 andoutlet port 812 are located on the same side of the cartridge 800. Theseports 810, 812 may be capable of an airtight seal and of being puncturedwhen the cartridge 800 is inserted into a receiving assembly/device ofthe odorant generator 100, allowing in flow of clean, filtered air, andout flow of saturated odorant. The ports 810, 812 may be high on theside of the cartridge 800 to prevent any possible liquid leaking liquidodorants that might be accumulating on the floor of the cartridge 800.

The illustrated cartridge 800 includes plungers 820 that are forcedinwardly when the cartridge 800 is inserted in a receivingassembly/device of the odorant generator 100. The plungers 820 areconfigured to mechanically break ampoules 900 (FIG. 9C), such as glassampoules, within the cartridge 800 to release liquid phase odorant ontothe absorbent material in the interior 802 of the cartridge 800.

The volume of the cartridge 800 may also serve as a reservoir for thesaturated gas phase odorant. If, for example, the cartridge 800 has avolume of 250 milliliters (ml), it might hold a sufficient volume ofsaturated gas phase odorant to create hundreds of stimulates atrelatively low concentrations.

As illustrated in FIG. 9B, the inside of the cartridge includes amaze-like structure 802 or a plurality of louvers 802, whichsignificantly increase the surface area. The interior structure of thecartridge 800 may be constructed of a wicking or absorbent materialconfigured to hold and disburse a liquid phase odorant. In someembodiments, the internal volume of the cartridge is between about80-320 milliliters and serves as a reservoir for multiple odorantstimuli. The odorant passes from the liquid phase to a gas phase throughdiffusion. The illustrated cartridge 800 includes an external circuitboard 804 and connection so that the cartridge 800 can be controlled andpowered by the computer 500 (FIG. 1). With the power from the computer500, a coil may be heated or an internal ultrasonicator may be activatedto aid in aerosolization. The cartridge 800 could be single use anddisposable, or multi use.

According to other embodiments of the present invention, the cartridge800 can have multiple spaces for different odorants or the same odorantin different concentrations.

According to other embodiments of the present invention, the cartridge800 can have a powered agitator or whisk to move the odorants around andaid in aerosolization.

According to other embodiments of the present invention, the cartridge800 can have a ultrasonicator/nebulizer to facilitate in aerosolization.

According to other embodiments of the present invention, the cartridge800 can have a heating filament for maintaining a desired temperature ofthe odorant to facilitate aerosolization.

Referring back to FIG. 1, exemplary signal amplifiers and signalamplifiers that may be utilized as the signal amplifier/processor 400are available from Tucker-Davis Technologies, Alachua, Fla. Exemplarysoftware for controlling the system 10 of FIG. 1, including signalprocessing and display via the display on computer 500, is alsoavailable from Tucker-Davis Technologies. In some embodiments of system10, the exemplary signal amplifier/processor 400 and computer 500 may beenclosed in the odorant generator 100 case as opposed to beingexternally connected. Other sources for equipment and software that maybe utilized in accordance with embodiments of the present invention areavailable from, for example, Cambridge Research Systems, Rochester,United Kingdom; Biopac Systems, Goleta, Calif.; Stoelting, Inc., WoodDale, Ill.; World Precision Instruments, Sarasota, Fla.; ThomasRecording GmbH, Giessen, Germany; Lafayette Instrument Company,Lafayette, Ind.; Scientifica, Uckfield, United Kingdom; Emotiv Inc., SanFrancisco, Calif.; Imotions, Boston, Mass.; Neurosky, San Jose, Calif.;Multi Channel Systems MCS GmbH, Reutlingen, Germany.

FIGS. 12A-12D, 13A-13C, 14, 15A-15N, 16A-16B and 17A-17F are exemplaryreports generated using data collected by embodiments of the presentinvention. FIG. 12A-12D illustrate exemplary OEP individual wave formdata that can be obtained using the system of FIG. 1. FIG. 12Aillustrates hypothetical raw OEP waveforms. FIG. 12B illustrateshypothetical OEP waveforms with measurement guides. FIG. 12C illustrateshypothetical group mean OEP waveforms for each nostril of a nose. FIG.12D illustrates hypothetical group grand mean OEP (averaged acrossnostril) waveforms.

FIGS. 13A-13C illustrate exemplary OERP individual topographical heatmap data that can be obtained using the system of FIG. 1. Thetopographic heat maps show voltage gradients at different times postodorant activation for a hypothetical subject, superimposed on astandard head. At 100 ms (FIG. 13A), the calculated OEP onset latency,the red zones indicates activation of the olfactory epithelium. Withincreases in latency from 100 ms to 400-800 ms, the site of activation(shades of red) indicate a shift in activation to deeper, more centralneural sites, likely olfactory bulb and piriform cortex.

FIG. 14 illustrates exemplary alpha wave oscillation data obtained usingthe system of FIG. 1. Alpha wave oscillation occurs when the brain isidling, resting, i.e., when unstimulated. When a stimulus is presented(odorant, auditory or vibrotactile), the brain is excited and the idling(alpha) oscillation is suppressed or desynchronized because the brain isnow attending to the new (odorant, auditory or vibrotactile) stimulus.The alpha oscillation was largest between 8 and 9 Hz, and a significantnegativity (shades of blue within the red circled alpha frequency band)indicate a suppression, or desynchronization, of alpha respondingbeginning just prior to odorant delivery. The alpha desynchronizationlikely preceded odorant onset due to the sounds generated by theactivation of the odorant delivery valves.

FIGS. 15A-15N illustrate exemplary alpha wave spectra grand mean datafrom a group of hypothetical subjects tested using the system of FIG. 1.Illustrated are topographic voltage gradient distribution of alpha wavespectra projected onto a standard head, with time course of changesfollowing odorant onset, grand mean average of six hypotheticalsubjects. Greater odorant ERP suppression in alpha peak amplitude isshown in shades of blue, and red shows an increase in alpha afterodorant cessation. Indicated time epochs have been affected by theanalysis procedure.

The alpha wave is present when the brain is idling and alert (it isthought to play a role in attention), but is suppressed when the brainis stimulated, in this case, by the odorant. Recent studies haverecently shown that this event-related change in alpha activity (e.g.,shown between the topographic maps −300 ms-173.3 and −173.2-−46.5; andfrom 714.5 ms-841.2 ms to 968.1 ms-1094.8 ms) is a sensitive biomarkerfor concussions (c.f., Arakaki et al., 2018; Guay et al., 2018, whichare incorporated herein by reference in their entireties).

FIGS. 16A-16B illustrate exemplary alpha band suppression grand meandata from a group of hypothetical subjects tested using the system ofFIG. 1. Examples of alpha suppression at different time points followingodorant stimulus onset. FIG. 16A illustrates response at an electrode onthe front of the head, where the alpha oscillation was largest (notedifference in scales for FIGS. 16A and 16B). In FIG. 16A, a significantnegativity (shades of blue within the red circled alpha frequency band)indicate a decrease in responding beginning just prior to odorantdelivery. The alpha suppression likely preceded odorant onset due to thesounds generated by the activation of the odorant delivery valves.

A suppression of the alpha response (frequency ˜9 Hz), though muchsmaller, is also observed in FIG. 16B for sensor Cz, on the vertex ofthe skull. Though smaller, the alpha suppression is demonstration of thealpha oscillation (prior to stimulus onset).

FIGS. 17A-17F illustrate exemplary multisensory data using the system ofFIG. 1. Locations of somatosensory and auditory activation voltagegradients (shades of red/yellow) are superimposed on a standard headmodel. Auditory and vibrotactile stimuli were activated simultaneously.Activation is located over auditory and somatosensory cortices.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. The invention is defined by the following claims, withequivalents of the claims to be included therein.

1. A system for measuring neurologic function of a subject, the systemcomprising: an odorant generator configured to deliver an odorantstimulation to the subject; an auditory generator configured to deliveran audible stimulation to the subject; at least one electrode configuredto be attached to the subject, wherein the at least one electrode isconfigured to collect neural signals from the subject as a result of theodorant stimulation and the audible stimulation; and at least oneprocessor configured to process the neural signals from the at least oneelectrode and generate an assessment of neurologic function of thesubject.
 2. The system of claim 1, further comprising a vibrotactilestimulator configured to generate a somatosensory stimulation to thesubject, and wherein the at least one electrode is configured to collectneural signals from the subject as a result of the somatosensorystimulation.
 3. The system of claim 1, wherein the at least oneelectrode comprises a plurality of electrodes configured to be attachedto the subject at respective different locations.
 4. The system of claim1, wherein the auditory generator is configured to deliver an audiblestimulation to the subject via one or more earbuds worn by the subject.5. The system of claim 2, wherein the vibrotactile stimulator isconfigured to generate a somatosensory stimulation to skin of thesubject.
 6. The system of claim 1, wherein the odorant generatorcomprises a handheld intranasal delivery assembly or a mask configuredto be placed over a face of the subject.
 7. A system for measuringneurologic function of a subject, the system comprising: an odorantgenerator configured to deliver an odorant stimulation to the subject;an auditory generator configured to deliver an audible stimulation tothe subject; a vibrotactile stimulator configured to generate asomatosensory stimulation to the subject; a plurality of electrodesconfigured to be attached to the subject at respective differentlocations, wherein the plurality of electrodes are configured to collectneural signals from the subject as a result of the odorant stimulation,the audible stimulation, and the somatosensory stimulation; and at leastone processor configured to process the neural signals from theplurality of electrodes and generate an assessment of neurologicfunction of the subject.
 8. The system of claim 7, wherein the auditorygenerator is configured to deliver an audible stimulation to the subjectvia one or more earbuds worn by the subject, and wherein thevibrotactile stimulator is configured to generate a somatosensorystimulation to skin of the subject.
 9. The system of claim 7, whereinthe odorant generator comprises a handheld intranasal delivery assembly.10. A method of measuring neurologic function of a subject, the methodcomprising: delivering an odorant stimulation to the subject; deliveringan audible stimulation to the subject; delivering a somatosensorystimulation to the subject; collecting neural signals from the subjectvia one or more electrodes attached to the subject as a result of theodorant stimulation, the audible stimulation, and the somatosensorystimulation; and processing the neural signals via at least oneprocessor to generate an assessment of neurologic function of thesubject.
 11. The method of claim 10, wherein the odorant stimulation,the audible stimulation, and the somatosensory stimulation are deliveredto the subject substantially at the same time.
 12. The method of claim10, wherein the odorant stimulation, the audible stimulation, and thesomatosensory stimulation are delivered to the subject sequentially. 13.The method of claim 10, wherein the audible stimulation and thesomatosensory stimulation are delivered to the subject before theodorant stimulation.
 14. The method of claim 10, wherein the audiblestimulation and the somatosensory stimulation are delivered to thesubject after the odorant stimulation.
 15. A system for measuring evokedpotentials, the system comprising: an air source configured to provide afirst stream of odorless control air; an odorant generator configured togenerate a second stream of odorized air; an intranasal deliveryassembly; a first valve coupled to the air source and to the intranasaldelivery assembly; a second valve coupled to the odorant generator andto the intranasal delivery assembly; a controller coupled to the firstand second valves, wherein the controller is configured to direct thefirst and second valves to selectively open and close such that thefirst stream of odorless control air and the second stream of odorizedair can be selectively directed to the intranasal delivery assembly todeliver an odorant stimulation to the subject via the intranasaldelivery assembly; and a plurality of electrodes configured to beattached to the subject at respective different locations, wherein eachelectrode is configured to collect neural signals from the subject. 16.The system of claim 15, wherein the air source is an air pump orpressurized air source.
 17. The system of claim 15, wherein the odorantgenerator is configured to generate the second stream of odorized airwith a defined odorant concentration.
 18. The system of claim 15,wherein the odorant generator is configured to generate the secondstream of odorized air with a selected one of a plurality of differentodorant concentrations.
 19. The system of claim 15, wherein thecontroller is configured to direct the first and second valves toselectively open and close such that the odorant stimulation has anabrupt onset.
 20. The system of claim 15, wherein the controller isconfigured to direct the first and second valves to selectively open andclose such that there is no perceptible disturbance of air flow to thesubject.
 21. The system of claim 15, wherein the intranasal deliveryassembly comprises: a first tube connected to the first valve; a secondtube connected to the second valve; a third tube in fluid communicationwith the first and second tubes via a first connector; first and seconddelivery tubes, each delivery tube comprising a proximal end and anopposite distal end, wherein the proximal end of each delivery tube isin fluid communication with the third tube via a second connector; and abung secured to the distal end of each delivery tube, wherein each bungis configured to be inserted into a respective nostril of the subject.22. The system of claim 21, wherein each bung comprises a generallycylindrical body, and wherein each bung comprises an outer surface ofconductive material.
 23. The system of claim 21, wherein the first andsecond connectors are Y-connectors.
 24. The system of claim 15, furthercomprising a signal processor configured to process the neural signalsfrom the plurality of electrodes and generate an assessment ofneurologic dysfunction of the subject.
 25. The system of claim 15,further comprising a signal amplifier configured to receive and amplifythe neural signals from the plurality of electrodes prior to processingby the signal processor.
 26. The system of claim 15, wherein the odorantgenerator comprises an odorant cartridge configured to aerosolize aliquid odorant contained therewithin.
 27. The system of claim 26,wherein the cartridge comprises a frangible container of the liquidodorant and a plunger configured to break the frangible container torelease the liquid odorant.
 28. A system for measuring neurologicfunction of a subject, the system comprising: an odorant generatorconfigured to deliver an odorant stimulation to the subject; at leastone electrode configured to be attached to the subject, wherein the atleast one electrode is configured to collect neural signals from thesubject as a result of the odorant stimulation; and at least oneprocessor configured to process the neural signals from the at least oneelectrode and generate an assessment of neurologic function of thesubject.
 29. The system of claim 28, wherein the at least one electrodecomprises a plurality of electrodes configured to be attached to thesubject at respective different locations.
 30. The system of claim 28,wherein the odorant generator comprises a handheld intranasal deliveryassembly or a mask configured to be placed over a face of the subject.